PMID- 26578266 OWN - NLM STAT- MEDLINE DCOM- 20160506 LR - 20160109 IS - 1521-0103 (Electronic) IS - 0022-3565 (Linking) VI - 356 IP - 2 DP - 2016 Feb TI - Histones Differentially Modulate the Anticoagulant and Profibrinolytic Activities of Heparin, Heparin Derivatives, and Dabigatran. PG - 305-13 LID - 10.1124/jpet.115.229823 [doi] AB - The antithrombin activity of unfractionated heparin (UFH) is offset by extracellular histones, which, along with DNA, represent a novel mediator of thrombosis and a structural component of thrombi. Here, we systematically evaluated the effect of histones, DNA, and histone-DNA complexes on the anticoagulant and profibrinolytic activities of UFH, its derivatives enoxaparin and fondaparinux, and the direct thrombin inhibitor dabigatran. Thrombin generation was assessed by calibrated automated thrombinography, inhibition of factor Xa and thrombin by synthetic substrates, tissue plasminogen activator-mediated clot lysis by turbidimetry, and thrombin-activatable fibrinolysis inhibitor (TAFI) activation by a functional assay. Histones alone delayed coagulation and slightly stimulated fibrinolysis. The anticoagulant activity of UFH and enoxaparin was markedly inhibited by histones, whereas that of fondaparinux was enhanced. Histones neutralized both the anti-Xa and anti-IIa activities of UFH and preferentially blocked the anti-IIa activity of enoxaparin. The anti-Xa activity of fondaparinux was not influenced by histones when analyzed by chromogenic substrates, but was potentiated in a plasma prothrombinase assay. Histones inhibited the profibrinolytic activity of UFH and enoxaparin and enhanced that of fondaparinux by acting on the modulation of TAFI activation by anticoagulants. Histone H1 was mainly responsible for these effects. Histone-DNA complexes, as well as intact neutrophil extracellular traps, impaired the activities of UFH, enoxaparin, and fondaparinux. Dabigatran was not noticeably affected by histones and/or DNA, whatever the assay performed. In conclusion, histones and DNA present in the forming clot may variably influence the antithrombotic activities of anticoagulants, suggesting a potential therapeutic advantage of dabigatran and fondaparinux over heparins. CI - Copyright (c) 2016 by The American Society for Pharmacology and Experimental Therapeutics. FAU - Ammollo, Concetta Tiziana AU - Ammollo CT AD - Department of Biomedical Sciences and Human Oncology, Section of General and Experimental Pathology (C.T.A., N.S., M.C., F.S.), and Section of Pharmacology (M.R.C), University of Bari "Aldo Moro," Bari, Italy. FAU - Semeraro, Nicola AU - Semeraro N AD - Department of Biomedical Sciences and Human Oncology, Section of General and Experimental Pathology (C.T.A., N.S., M.C., F.S.), and Section of Pharmacology (M.R.C), University of Bari "Aldo Moro," Bari, Italy. FAU - Carratu, Maria Rosaria AU - Carratu MR AD - Department of Biomedical Sciences and Human Oncology, Section of General and Experimental Pathology (C.T.A., N.S., M.C., F.S.), and Section of Pharmacology (M.R.C), University of Bari "Aldo Moro," Bari, Italy. FAU - Colucci, Mario AU - Colucci M AD - Department of Biomedical Sciences and Human Oncology, Section of General and Experimental Pathology (C.T.A., N.S., M.C., F.S.), and Section of Pharmacology (M.R.C), University of Bari "Aldo Moro," Bari, Italy. FAU - Semeraro, Fabrizio AU - Semeraro F AD - Department of Biomedical Sciences and Human Oncology, Section of General and Experimental Pathology (C.T.A., N.S., M.C., F.S.), and Section of Pharmacology (M.R.C), University of Bari "Aldo Moro," Bari, Italy brizioraro@hotmail.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151117 PL - United States TA - J Pharmacol Exp Ther JT - The Journal of pharmacology and experimental therapeutics JID - 0376362 RN - 0 (Anticoagulants) RN - 0 (Fibrinolytic Agents) RN - 0 (Histones) RN - 9005-49-6 (Heparin) RN - EC 3.4.21.5 (Thrombin) RN - EC 3.4.21.6 (Factor Xa) RN - I0VM4M70GC (Dabigatran) SB - IM MH - Animals MH - Anticoagulants/*metabolism/pharmacology MH - Bothrops MH - Cattle MH - Dabigatran/*metabolism/pharmacology MH - Dose-Response Relationship, Drug MH - Factor Xa/metabolism MH - Female MH - Fibrinolytic Agents/*metabolism/pharmacology MH - Heparin/*metabolism/pharmacology MH - Histones/*metabolism/pharmacology MH - Humans MH - Male MH - Thrombin/antagonists & inhibitors/metabolism EDAT- 2015/11/19 06:00 MHDA- 2016/05/07 06:00 CRDT- 2015/11/19 06:00 PHST- 2015/10/05 00:00 [received] PHST- 2015/11/16 00:00 [accepted] PHST- 2015/11/19 06:00 [entrez] PHST- 2015/11/19 06:00 [pubmed] PHST- 2016/05/07 06:00 [medline] AID - jpet.115.229823 [pii] AID - 10.1124/jpet.115.229823 [doi] PST - ppublish SO - J Pharmacol Exp Ther. 2016 Feb;356(2):305-13. doi: 10.1124/jpet.115.229823. Epub 2015 Nov 17.